Estrogen hormone action within target tissues involves the interaction of the hormonal substance with a receptor protein. The specificity and responsiveness of tissues to hormonal stimulation are governed in most part by the presence and biochemical action of this receptor protein. Nuclear localization of the receptor and its activity was increased by exposure to growth factors, suggesting a coupling of these two signaling pathways. Gene regulation studies using mutant receptors show that growth factors regulate activity through the N-terminus of the receptor while estrogen acts through the C-terminus. Receptor mutants also demonstrated that DNA binding is required for the coupled activation. Use of the estrogen receptor recessive mice has supported the coupling as an in vivo mechanism, since EGF treatment did not stimulate uterine DNA synthesis in the absence of a functional estrogen receptor. Characterization of the EGF signalling pathway in the mice indicates EGF receptor levels and functionality are not altered compared to controls. Transgenic mice are being used to investigate the role of ER in normal physiological endocrine function and hormonal carcinogenesis. A mouse line (MT-ER) was created where ER is over-expressed in tissues, not normally possessing the receptor, to determine if its presence alters tissue and cell physiology and if these tissues are now more susceptible to hormonal carcinogenesis. Findings with this MT-MER line show altered reproductive phenotypes of dystocia which is relevant to human conditions of delayed parturition. Neonatal DES treatment to MT-MER mice results in early advancement of the tumorigenicity from 12-14 mos in nontransgenic to 6 mos in MT-MER. The tumor incidence is increased to 73% at that time compared to 50% at 12 mos in the nontransgenic. This is the first description of the correlative role for estrogen receptor expression and increased hormonal tumorigenicity. A possible increase in lung tumors is being analyzed. Another transgenic approach is the production of a homozygous recessive ER mutant mouse line (ERKO). Analysis of the recessives shows both sexes are infertile. Reproductive tract structures are present, but alterations to gonadal tissues are evident where testis are dysmorphogenic with few germ cells and a 10% sperm count; females have hypoplastic uteri, hyperemic cystic ovaries similar to the condition of polycystic ovary syndrome in humans. Currently, these experimental animals are being further characterized for determining their use as a model system for evaluating the role of estrogen receptor mechanisms in male and female reproductive biology and fertility. The first patient with estrogen insensitivity has been described and the loss of function gene mutations characterized for this clinical syndrome.